Substituted 9-(1 or 3-monoacyloxy or 1,3-diacyloxy-2-propoxymethyl) purines as antiviral agent

ABSTRACT

Compounds useful as antiviral agents are defined by the following formula: ##STR1## and the pharmaceutically acceptable acid addition salts thereof wherein R 1  is hydrogen or --C(O)R 7  wherein R 7  is hydrogen, alkyl of one to nineteen carbon atoms, hydroxyalkyl of one to eight carbon atoms, alkoxyalkyl of two to nine carbon atoms, alkenyl of two to nineteen carbon atoms, phenyl, 1-adamantyl or 2-carboxyethyl and the pharmaceutically acceptable alkali metal salts thereof; 
     R 2  is --C(O)R 7  wherein R 7  is as defined above; 
     R 3  is hydrogen, halo, thio, lower alkylthio of one to six carbon atoms, azido, NR 9  R 10  wherein R 9  and R 10  are independently hydrogen or lower alkyl of one to six carbon atoms or --NHC(O)R 8  wherein R 8  is hydrogen, alkyl of one to nineteen carbon atoms or 1-adamantyl; and 
     (a) R 6  is hydrogen, halo, lower alkoxy of one to six carbon atoms, azido, thio, lower alkylthio of one to six carbon atoms, --NR 9  R 10  wherein R 9  and R 10  are as defined above or --NHC(O)R 8  wherein R 8  is as defined above and R 4  together with R 5  is a bond; or 
     (b) R 5  together with R 6  is a keto group and R 4  is hydrogen.

This is a continuation-in-part of U.S. Ser. No. 344,703 filed Feb. 1,1982 now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to substituted 9-(1 or 3-monoacyloxy or1,3-diacyloxy-2-propoxymethyl)purines and pharmaceutically acceptableacid addition salts thereof which are useful as antiviral agents. Theinvention also relates to a pharmaceutical composition containing theabove compounds in combination with a suitable non-toxic carrier, thecomposition being useful in combatting viral infections. The inventionalso relates to a process for preparing the compounds of the invention.

2. Related Disclosure

Viral infections are widespread and result in a wide variety ofsymptoms. Some viral infections are easily overcome by the body'sdefense mechanism, but when this defense mechanism is impaired theseinfections can lead to permanent damage, e.g., blindness, and even todeath. One such family of viruses which may cause serious infections isthe herpes virus group.

The drugs presently used to treat viral infections are ineffective inmany cases or, if effective, are needed in large and/or continuousdosages which produce serious side-effects and/or toxicity. Thereforethere is a need for an effective antiviral agent which is effective atlower dosages than the presently available drugs, thus diminishing thechance of possible side-effects and toxicity.

U.S. Pat. No. 4,199,574 discloses compounds represented by the followinggeneric formula: ##STR2## wherein X is sulphur or oxygen, R¹ ishydrogen, halogen, hydroxy, alkoxy, azide, thio, alkylthio, amino,alkylamino or dialkylamino; R² is hydrogen, halogen, alkylthio,acylamino, amino or azide; R³ is hydrogen, straight or branch chain orcyclic alkyl, hydroxyalkyl, benzyloxyalkyl or phenyl; R⁴ is hydrogen,hydroxy or alkyl; R⁵ is hydrogen, hydroxy, amino, alkyl, hydroxyalkyl,benzyloxy, benzoyloxy, benzoyloxymethyl, sulphamoyloxy, phosphate,carboxypropiamyloxy, straight chain or cyclic acyloxy having from 1 to 8carbon atoms e.g., acetoxy or substituted carbamoyl group of formulaNHCO-Z wherein Z is alkyl, aryl or aralkyl optionally substituted by oneor more of sulphonyl, amino, carbamoyl or halogen; R⁶ is hydrogen oralkyl, provided that when X is oxygen and R², R³, R⁴, and R⁶ arehydrogen, R¹ is not amino or methylamino when R⁵ is hydrogen or hydroxy,or a salt thereof.

The class of compounds represented by the above formula and thepharmaceutically acceptable acid addition salts thereof are described toexhibit antiviral activity. See also Tetrahedron Letters, 21, 327-30(1980), U.S. Pat. No. 4,294,831 and U.S. Pat. No. 4,347,360.

SUMMARY OF THE INVENTION

It has now been discovered that substituted 9-(1 or 3-monoacyloxy- or1,3-diacyloxy-2-propoxymethyl)purines and the salts thereof areparticularly active antiviral agents.

The first aspect of the present invention is the compound of thefollowing formula: ##STR3## and the pharmaceutically acceptable acidaddition salts thereof wherein

R¹ is hydrogen or --C(O)R⁷ wherein R⁷ is hydrogen, alkyl of one tonineteen carbon atoms, hydroxyalkyl of one to eight carbon atoms,alkoxyalkyl of two to nine carbon atoms, alkenyl of two to nineteencarbon atoms, phenyl, 1-adamantyl or 2-carboxyethyl and thepharmaceutically acceptable alkali metal salts thereof;

R² is --C(O)R⁷ wherein R⁷ is as defined above;

R³ is hydrogen, halo, thio, lower alkylthio of one to six carbon atoms,azido, NR⁹ R¹⁰ wherein R⁹ and R¹⁰ are independently hydrogen or loweralkyl of one to six carbon atoms or --NHC(O)R⁸ wherein R⁸ is hydrogen,alkyl of one to nineteen carbon atoms or 1-adamantyl; and

(a) R⁶ is hydrogen, halo, lower alkoxy of one to six carbon atoms,azido, thio, lower alkylthio of one to six carbon atoms, --NR⁹ R¹⁰wherein R⁹ and R¹⁰ are as defined above or --NHC(O)R⁸ wherein R⁸ is asdefined above and R⁴ together with R⁵ is a bond; or

(b) R⁵ together with R⁶ is a keto group and R⁴ is hydrogen.

Another aspect of the invention relates to pharmaceutical compositionsfor antiviral use comprising the compounds of the instant invention anda suitable carrier.

A further aspect of the invention is a method of treating viralinfections consisting of administering a compound of the presentinvention or a composition containing same.

Another aspect of the invention are the novel compounds of formulas(IXa) and (XIV)(infra) wherein A is hydrogen which are useful asintermediates and as antiviral agents.

Yet another aspect of the invention is a process for preparing thecompounds of formula (I) which comprises esterifying a compound offormula (X) or (XIV) infra.

DETAILED DESCRIPTION AND PREFERRED EMBODIMENT

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated.

The term "alkyl" refers to a straight or branched chain monovalentsubstituent consisting solely of carbon and hydrogen, containing nounsaturation and having one to nineteen carbon atoms. Examples of alkylare methyl, n-butyl, 2-methyl-2-propyl, n-octyl, n-decyl, n-tetradecyland n-nonadecyl. The term "lower alkyl" refers to alkyl groups asdefined above but containing one to six carbon atoms. The term "alkenyl"refers to a straight or branched chain monovalent substituent consistingsolely of carbon and hydrogen, containing one or more double bonds andhaving two to nineteen carbon atoms. Examples of "alkenyl" are propenyl,pentenyl, heptenyl, dodecenyl, dodecadienyl, pentadecenyl andpentadecadienyl. The term "1-adamantyl" refers to the following ringstructure. ##STR4## "Lower alkoxy" refers to "lower alkyl-O-" wherein"lower alkyl" is as defined above. Examples of "lower alkoxy" aremethoxy, ethoxy, i-butoxy and n-hexyloxy. The term "alkoxyalkyl" refersto alkyl-O-alkylene wherein alkyl is as defined above and alkylene is adivalent alkyl group. Examples of "alkoxyalkyl" are methoxymethyl,i-propoxymethyl, n-octanyloxymethyl and ethoxypropyl. The term "loweralkylthio" refers to "lower alkyl-S-" wherein "lower alkyl" is asdefined above. Examples of "lower alkylthio" are methylthio,n-propylthio and n-pentylthio. "Thio" refers to --SH. "Amino" refers to--NH₂. "Azido" refers to N₃. "Halo" refers to fluoro, chloro and bromo."2-Carboxyethyl" refers to HOOCCH₂ CH₂ --.

"Pharmaceutically acceptable acid addition salts" refers to those saltswhich possess the biological effectiveness and properties of the freecompound and which are not biologically or otherwise undesirable.Suitable acids for salt formation are inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid andthe like, and organic acids such as trifluoroacetic acid,menthanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid andthe like.

"Pharmaceutically acceptable alkali metal salts" refers to the metalsalts of the free carboxy group of the carboxyethyl group. Examples ofalkali metals are sodium and potassium.

Compounds of formula (I) wherein R¹ is hydrogen and R² is C(O)R⁷ containan assymetric carbon atom. Accordingly, these compounds may be preparedin either optically active form, or as a racemic mixture. Unlessotherwise specified, the monoesters of formula (I) described herein areall in the racemic form. However, the scope of the subject invention isnot to be considered limited to the racemic form, but to encompass theindividual optical isomers of the monoesters of formula (I).

It is to be understood that the definition of R⁵ together with R⁶ asketo includes the tautomeric hydroxy form but for convenience the ketoform will be used to represent both tautomeric forms.

A preferred group of compounds of formula (I) is that wherein R³ isamino, R⁴ is hydrogen and R⁵ together with R⁶ is keto (compounds offormula (Ia) infra). Another preferred group of compounds of formula (I)is that wherein R³ is amino and R⁶ is hydrogen, thio or NH₂ and R⁴together with R⁵ is a bond. A preferred subgroup within these groups isthat wherein R¹ and R² are both --C(O)R⁷. A more preferred subgroup isthat wherein R⁷ is alkyl of one to five carbon atoms with R⁷ beingmethyl or ethyl being most preferred. Another preferred subgroup withinthese groups is that wherein R¹ is hydrogen and R² is --C(O)R⁷. A morepreferred subgroup within this subgroup is that wherein R⁷ is alkyl ofone to five carbon atoms with R⁷ being methyl or ethyl being the mostpreferred.

UTILITY AND ADMINISTRATION

The subject compound of formula (I) and the pharmaceutically acceptablesalts thereof exhibit potent antiviral activity when administered towarm blooded and cold blooded animals, particularly mammals, birds, andfish, but most particularly humans. For example, the compound of thepresent invention exhibits excellent activity against Herpes Simplexvirus I and II and related viruses such as cytomegalovirus, Epstein-Barrvirus and varicella Zoster virus as well as viral hepatitis such ashepatitis B. Compounds of formula (I) wherein R¹ and R² are --C(O)R⁷wherein R⁷ is ethyl, i.e., the dipropanoate ester exhibits propertieswhich make it particularly suitable for the treatment of viralinfections. This ester is more soluble in aqueous solutions than wouldbe expected from the solubility of the adjacent homologs, thus makingthe dipropanoate ester particularly suitable for parenteraladministration. Further, the dipropanoate is more bioavailable.

Pharmaceutical compositions, both veterinary and human, containing thesubject compound appropriate for antiviral use are prepared by methodsand contain excipients which are well known in the art. A generallyrecognized compendium of such methods and ingredients is Remington'sPharmaceutical Sciences by E. W. Martin, (Mark Publ. Co., 15th Ed.,1975). Liposomes may also be employed as pharmaceutical compositions forthe compounds of formula (I), using methods known in the art [forexample, as described in Szoka, F. Jr., et al, Ann. Rev. Biophys.Bioeng. 9:467-508 (1980), Schullery, S. E. et al, Biochemistry19:3919-23 (1980) and Gregoriadin, G. et al, "Liposomes in BiologicalSystems:", John Wiley and Sons (1980)].

The compound of the invention may be administered parenterally (forexample, by intraveneous, subcutaneous, intraperitoneal or intramuscularinjection), orally, topically, rectally or intranasally.

The compositions are administered orally or parenterally at dose levels,calculated as the free base, of about 0.1 to 300 mg/kg, preferably 1.0to 30 mg/kg of mammal body weight, and are used in man in a unit dosageform, administered one to five times daily in the amount of 1 to 500 mgper unit dose. For oral administration, fine powders or granules maycontain diluting, dispersing and/or surface active agents, and may bepresented in a draught, in water or in a syrup; in capsules or sachetsin the dry state or in a non-aqueous solution or suspension, whereinsuspending agents may be included; in tablets, wherein binders andlubricants may be included; in a suspension in water or a syrup; or inan aerosol. Where desirable or necessary, flavoring, preserving,suspending, thickening or emulsifying agents may be included. Tabletsand granules are preferred, and these may be coated. The amount ofcompound of formula (I) in the formulation may vary from 0.1 percentweight (%w) to 99%w or more of the compound based on the totalformulation and about 1%w to 99.9%w excipient. Preferably the compoundis present at a level of 10%-95%w.

For parenteral administration or for administration as drops, as for eyeinfections, the compounds may be presented in aqueous solution in aconcentration of from about 0.1 to 10%, more preferably about 0.1 to 7%.The solution may contain antioxidants, buffers, and other suitableadditives.

Alternatively for infections of the eye, or other external tissues, e.g.mouth and skin, the compositions are preferably applied to the infectedpart of the body of the patient topically as an ointment, cream, aerosolor powder, preferably in an ointment or cream. The compounds may bepresented in an ointment, for instance with a water soluble ointmentbase, or in a cream, for instance with an oil in water cream base, in aconcentration of from about 0.01 to 10%; preferably 0.1 to 7%, mostpreferably about 3.0% w/v. Additionally, viral infections may be treatedby use of a sustained release drug delivery system as is described inU.S. Pat. No. 4,217,898.

For aerosol administration, the active ingredient is preferably suppliedin finely divided form along with a surfactant and a propellant. Typicalpercentages of active ingredients are 0.01 to 20% by weight, preferably0.04 to 1.0%.

Surfactants must, of course, be non-toxic, and preferably soluble in thepropellant. Representative of such agents are the esters or partialesters of fatty acids containing from 6 to 22 carbon atoms, such ascaproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic,olestearic and oleic acids with an aliphatic polyhydric alcohol or itscyclic anhydride such as, for example, ethylene glycol, glycerol,erythritol, arabitol, mannitol, sorbitol, the hexitol anhydrides derivedfrom sorbitol (the sorbitan esters sold under the trademark "Spans") andthe polyoxyethylene and polyoxypropylene derivatives of these esters.Mixed esters, such as mixed or natural glycerides may be employed. Thepreferred surface-active agents are the oleates or sorbitan, e.g., thosesold under the trademarks "Arlacel C" (Sorbitan sesquioleate), "Span 80"(sorbitan monooleate) and "Span 85" (sorbitan trioleate). The surfactantmay constitute 0.1-20% by weight of the composition, preferably 0.25-5%.

The balance of the composition is ordinarily propellant. Liquefiedpropellants are typically gases at ambient conditions, and are condensedunder pressure. Among suitable liquefied propellants are the loweralkanes containing up to five carbons, such as butane and propane; andpreferably fluorinated or fluorochlorinated alkanes, such as are soldunder the trademark "Freon." Mixtures of the above may also be employed.

In producing the aerosol, a container equipped with a suitable valve isfilled with the appropriate propellant, containing the finely dividedactive ingredient and surfactant. The ingredients are thus maintained atan elevated pressure until released by action of the valve.

The compounds of the present invention or compositions containing sameare also useful in treating non-human mammals, birds, e.g., chickens andturkeys, and cold-blooded animals, e.g., fish. For example, thecompounds of the present invention and compositions containing sameexhibit antiviral activity against the following non-human viruses:

Sciruid herpesvirus 1

Cavlid herpesvirus 1

Lagomorph herpesvirus 1

Phasianid herpesvirus 1

Phasianid herpesvirus 2 (Marek's disease)

Turkey herpesvirus 1

Anatid herpesvirus 1

Catfish herpesvirus 1

Equid herpesvirus 3

Bovid herpesvirus 1

Bovid herpesvirus 2

Bovid herpesvirus 3

Bovid herpesvirus 4

Pig herpesvirus 1

Pig herpesvirus 2

Murid herpesvirus 1

Cebid herpesvirus 1

Cebid herpesvirus 2

Tupaiid herpesvirus 1

Canine herpesvirus 1

Feline herpesvirus 1

Equid herpesvirus 1

Equid herpesvirus 2

Avian viral diseases such as Marek's disease and the like are preventedand/or treated by compounds of the present invention by methodswell-known in the veterinary art such as by injecting the birds with thecomposition containing the compound, or by adding the compound of theinstant invention to feed or drinking water.

Fish which are in a confined area such as a pool, aquarium or holdingtank may also be treated for viral infections such as herpeslikeviruses, e.g., channel catfish virus (CCV), herpes-virus salomones,Nerka virus and the like by adding the compound directly to the water ofthe pool, aquarium or holding tank or by incorporating the compoundsinto the feed.

The exact regimen for administration of the compounds and compositionsdisclosed herein will necessarily be dependent upon the needs of theindividual subject being treated, the type of treatment and, of course,the judgement of the attending practitioner.

PREPARATION

The compounds of formula (I) may be prepared from compounds of formula(X) (infra) and compounds of formula (XIV) wherein A is hydrogen (infra)which compounds are prepared by Reaction Sequence Ib. Intermediate offormula (V), which is used in Reaction Sequence Ib, is prepared byReaction Sequence Ia. ##STR5## wherein A is hydrogen or acetyl and R³and R⁶ are defined in the following table:

    ______________________________________                                                     R.sup.3    R.sup.6                                               ______________________________________                                        a)             NH.sub.2     OR                                                b)             NH.sub.2     SH                                                c)             N.sub.3      N.sub.3                                           d)             NH.sub.2     NH.sub.2                                          e)             Cl           NH.sub.2                                          f)             N.sub.3      NH.sub.2                                          g)             NH.sub.2     H                                                 h)             H            NH.sub.2                                          i)             H            SH                                                j)             SH           NH.sub.2                                          ______________________________________                                    

In Reaction Sequence Ia, the compound of formula (III) is prepared byadding epichlorohydrin (II) dropwise to a solution of an alkali metalsalt, preferably the sodium salt, of optionally substituted benzylalcohol in a solvent such as dimethylformamide, dimethylacetamide,hexamethylphosphoramide, dimethylsulfoxide, sulfolane, tetrahydrofuran,and dioxane at a temperature of about 0° C. to 100° C., preferably atabout 15° C. to 40° C. The reaction mixture is stirred for about 10hours to 24 hours, preferably for about 12 hours to 18 hours at atemperature of about 0° C. to 100° C., preferably from about 20° C. to50° C.

Compound of formula (III) is chloromethylated to compound of formula(IV) by bubbling dry hydrogen chloride gas in a solution of the compoundand paraformaldehyde dissolved in a halogenated hydrocarbon solvent suchas dichloroethane, chloroform, dichloromethane, or 1,1,2-trichloroethanecooled to a temperature of about 0° C. to 25° C., preferably at atemperature of about 0° C. The hydrogen chloride gas is added over 30minutes to 3 hours, preferably over 1 hour to 2 hours until theparaformaldehyde dissolves. The solution is held at a temperature fromabout 0° C. to 10° C. for about 12 hours to 48 hours, preferably fromabout 0° to 5° C. for about 16 hours to 24 hours.

Compound of formula (V) is prepared by reacting an alkali metal acetatesuch as sodium acetate with compound of formula (IV) dissolved in asolvent such as dimethylformamide, tetrahydrofuran, dimethylacetamide,hexamethylphosphoramide, dimethylsulfoxide, sulfolane, and dioxane at atemperature of about 0° C. to 45° C., preferably from about 0° C. to 25°C. The solution is stirred from about 5 to about 24 hours, preferablyfrom about 10 hours to about 18 hours at a temperature of about 10° C.to about 30° C., preferably at a temperature of about 15° C. to 25° C.

In Reaction Sequence Ib, compound of formula (VII) is prepared byheating guanine (VI) with acetic anhydride, neat, at reflux for about 10to 24 hours, preferably for about 12 to 18 hours.

N²,9-Diacetylguanine of formula (VII) is reacted with compound offormula (V) to form compound of formula (VIII) neat or in a solvent suchas dioxane, sulfolane and the like in the presence of a catalytic amountof an acid such as bis(p-nitrophenyl)phosphate, toluenesulfonic acid,methylphosphonic acid or dichloroacetic acid, preferablybis(p-nitrophenyl)phosphate at a temperature of about 75° C. to 200° C.,preferably at about 110° C. to 180° C. The reaction is generally carriedout using 0.8 moles to 1.2 moles of compound of formula (V) to one moleof compound of formula (VII).

The benzyl protecting groups are removed from compound of formula (VIII)by catalytic hydrogenation to form compound of formula (IX). A catalystsuch as palladium on carbon in a slurry is added to a solution ofcompound of formula (VIII) dissolved in a solvent such as aqueousmethanol. Hydrogen is added to the solution at a pressure of 15 psi to200 psi, preferably at a pressure of 30 psi to 80 psi.

Compound of formula (X) is prepared by deacetylating compound of formula(IX) with a base such as ammonia dissolved in an alcohol such asmethanol. A solution of compound of formula (IX) and the base is stirredfor about 5 hours to 36 hours, preferably for about 10 hours to 24 hoursat a temperature of about 10° C. to 30° C., preferably at a temperatureof about 15° C. to 25° C.

Compound of formula (X) may be esterified to the diacetate of formula(XI) by reacting compound of formula (X) with excess acetic anhydride,either neat or in a solvent such as dimethylformamide, dimethylacetamideand the like at room temperature for two to three days.

Compound of formula (XII) may be prepared by reacting compound offormula (XI) with phosphorus oxychloride according to the methoddescribed in J. Org. Chem. 28:945, 1963. Compound of formula (XI) isadded to a solution of phosphorus oxychloride in N,N-diethylaniline atroom temperature. The suspension is heated at reflux for 2 to 30minutes, preferably from 2 to 5 minutes. The excess phosphorusoxychloride is removed and the product recovered by conventional meanssuch as extraction with an organic solvent followed by chromatography.

Compound of formula (XII) may be further chlorinated by forming thediazo salt with sodium nitrite in hydrochloric acid as described in J.Org. Chem. 31:3258, 1966. To compound of formula (XII) in aqueoushydrochloric acid is added sodium nitrite in water at 0° to 5° C. Thesolution is diluted with water and the excess hydrochloric acid isneutralized with aqueous ammonia and compound of formula (XIII) isrecovered by methods well known in the art such as extraction with anorganic solvent followed by chromatography.

Compounds of formula (XIV) may be prepared from compounds of formulas(XII) and (XIII) by methods well known in the art. See, for example,"Heterocyclic Compounds--Fused Pyrimidines Part II Purines, Ed. D. J.Brown (1971) Wiley-Interscience" and U.S. Pat. No. 4,199,574 whichpatent is incorporated herein by reference. See preceding table forcompounds of formula (XIV)a-j.

Compound of formula (XIVb) wherein A is hydrogen may be prepared byreacting a compound of formula (XII) with thiourea dissolved in asolvent such as isopropanol with heating at reflux for one to two hours.The thiourea adduct which forms is broken down with an alkali such asaqueous ammonia yielding the thio compound. The reaction also leads tothe hydrolysis of the ester groups.

Compounds of formula (XIVa) wherein A is hydrogen and R is lower alkylare prepared from compound of formula (XII) by treatment with analcoholic solution of the appropriate alkali metal alkoxide such assodium methoxide in methanol at room temperature or with mild heating.

Various compounds of formula (XIV) may be prepared from compound offormula (XIII). For example, compound of formula (XIVc) wherein A isacetyl is prepared by treating compound of formula (XIII) with sodiumazide in a solvent such as ethanol:water, dimethylformamide,hexamethylphosphoramide and the like. The reactants are heated for twoto 24 hours at 80° to 200° C. Compound of formula (XIVd), wherein A ishydrogen, are prepared by hydrogenating compound of formula (XIVc)using, for example, a palladium on charcoal catalyst.

Compound of formula (XIII) is converted to compound of formula (XIVe)wherein A is hydrogen by heating compound of formula (XIII) and ammoniadissolved in methanol in a bomb for 16 to 24 hours at 85° to 110° C. Theabove compound may be further ammoniated by heating compound of formula(XIVe) dissolved in liquid ammonia in a bomb for 24 to 48 hours at 110°to 150° C. to form compound of formula (XIVd) wherein A is hydrogen.

Another method of preparing compound of formula (XIVd) is by treatingcompound of formula (XIVe) with hydrazine and then with a cold solutionof sodium nitrite to form compound of formula (XIVf) wherein A ishydrogen, which in turn is hydrogenated to the compound of formula(XIVd) using, for example, a palladium on charcoal catalyst.

The amino groups of compounds of formula (XIV) wherein R³ and/or R⁶ isamino may be alkylated to the secondary or tertiary amines by treatmentwith an alkyl halide such as methyl iodide. A preferred method forpreparing the above alkylated amino compounds is by reacting a compoundof formula (XIII) or (XIVe) with an alkyl or dialkyl amine.

Compounds of formula (IXa) wherein R⁸ is other than methyl may beprepared by protecting the hydroxy groups of compound of formula (IX)with a trityl protecting agent as defined infra, deacetylating the aminonitrogen, reacting the deacetylated compound with the appropriate acidchloride and removing the protecting groups with glacial aceticacid:water.

Those compounds of formula (XIV) wherein A is acetyl may be hydrolyzedby methods well known in the art such as by acidic or basic hydrolysis.

Compounds of formulas (XIVg) and (XIVh) may be prepared by thehydrogenation of compounds of formulas (XII) and (XIVe) respectivelyusing a hydrogenation catalyst such as palladium in the presence of abase such as magnesium dioxide.

Compound of formula (XIVi) wherein A is hydrogen is prepared by reactingcompound of formula (XIVh) with sodium nitrite in acetic acid to formthe 6-keto compound which in turn is chlorinated with a chlorinatingagent such as phosphoryl chloride, phosphorous pentachloride and thelike by methods well known in the art. The 6-chloro intermediate istreated with thiourea as described above.

Compounds of formula (XIVj) may be prepared, for example, by reactingcompound of formula (XIVe) with methanolic hydrogen sulfide-ammoniumcarbonate as described in J. Org. Chem., 39(9):1256, 1974 or with sodiummercaptide in dimethylformamide as described in J. Med. Chem.,16(12):1381, 1973.

Compounds of formula (XIV) wherein R³ or R⁶ is thio may be alkylatedwith an alkyl halide such as an alkyl iodide in a solvent such as analkanol at room temperature.

The following compounds of formula (XIV) wherein A is hydrogen, forexample, may be prepared by one or a combination of the methodsdiscussed above:

2-amino-6-methoxy-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-methylamino-6-ethoxy-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-amino-6-thio-9-(1,3-dihydroxy-2-propoxymethyl)purine, m.p. 155°-157°C.;

2-n-butylamino-6-thio-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-amino-6-methylthio-9-(1,3-dihydroxy-2-propoxymethyl) purine;

2-dimethylamino-6-methylthio-9-(1,3-dihydroxy-2propoxymethyl)purine;

2,6-diazido-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2,6-diamino-9-(1,3-dihydroxy-2-propoxymethyl)purine, m.p. 174°-180° C.;

2-methylamino-6-amino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-amino-6-methylamino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2,6-di(methylamino)-9-(1,3-dihydroxy-2-propoxymethyl)purine;

6-chloro-2-amino-9-(1,3-dihydroxy-2-propoxymethyl)purine, m.p.197.5°-198.5° C.;

2-chloro-6-methylamino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-azido-6-ethylamino-9-(1,3-dihydroxy-2-propoxymethyl)purine

2-amino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-methylamino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-dimethylamino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

6-amino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

6-methylamino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

6-dimethylamino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

6-thio-9-(1,3-dihydroxy-2-propoxymethyl)purine;

6-methylthio-9-(1,3-dihydroxy-2-propoxymethyl)purine; and

6-amino-2-thio-9-(1,3-dihydroxy-2-propoxymethyl)purine.

Diesters of formula (I) may be prepared by esterification methods wellknown in the art. For example, diesters of formula (I) wherein R⁷ islower alkyl may be prepared by reacting compounds of formula (X) and(XIV) wherein A is hydrogen with an excess of the appropriate acidanhydride, either neat or in a solvent such as dimethylformamide,dimethylacetamide, N-methylpyrrolidine and the like. The reactants arestirred for one to five days, preferably for two to three days at 0° to50° C., preferably at room temperature in the presence of a catalyst,e.g., 4-dimethylaminopyridine. Compounds of formula (X) or (XIV) and theacid anhydride are in a molar ratio of approximately 1:10-100.

The acid anhydrides are readily available or if not readily availablemay be prepared by methods well known in the art such as by heating theacid in the presence of acetic anhydride or acetyl chloride.

The diesters of formula (I) wherein R⁷ is hydrogen may be prepared bythe above described method using the mixed anhydride of formic acid andacetic acid, which may be prepared by reacting formic acid with aceticanhydride, neat, at 0° to 40° C.

Another method for preparing the diesters of formula (I) for all valuesof R⁷ is by first treating compound of formula (XI) or (XIV) wherein Ais acetyl and R³ and/or R⁶ is amino with a trityl protecting agent suchas triphenylmethyl chloride (trityl chloride),4-methoxyphenyldiphenylmethyl chloride (mono-methoxytritylchloride) andthe like. The trityl protecting agents are readily available from, i.a.,Aldrich Chemical Co.. The reactants in a solvent such asdimethylformamide, pyridine, and the like with a catalyst e.g.,4-dimethylpyridine are heated at 40° to 70° C., preferably at 45° to 60°C. for 8 to 24 hours, preferably for 12 to 18 hours. The amino protectedcompound is isolated by conventional means such as crystallization andthe acetate groups are hydrolyzed with a base, such as an alkali metalhydroxide, e.g., sodium hydroxide and potassium hydroxide, or withammonium hydroxide. The dihydroxy compound and a catalyst such as4-dimethylaminopyridine in pyridine is added dropwise to the appropriateacid chloride either neat or in a solvent such as methylene chloride,dichloroethane and the like. The reactants are stirred at roomtemperature for 10 to 24 hours, preferably from 12 to 18 hours. Theproduct is isolated by methods well known in the art such aschromatography. The amino protective groups are removed by treatmentwith an organic acid such as glacial acetic acid, trifluoroacetic acidand the like with heating from 60° to 100° C., preferably from 60° to80° C. for one to twelve hours, preferably from one to five hours. Theproduct is isolated by chromatography or crystallization.

The amino group(s) of the above described compound of formulas (XI) and(XIV) may also be protected by reacting the compounds with the acetal ofN,N-dimethyl formamide available from, i.a., Aldrich Chemical Co. andthen proceeding as discussed above.

The acid chlorides are readily available or if not readily available maybe prepared by reacting the appropriate acid with a chlorinating agentsuch as phosphorus trichloride, phosphorus pentachloride, or thionylchloride under reaction conditions well known in the art.

Diesters of formula (I) wherein R³ is amino, R⁵ together with R⁶ is ketoand R⁴ is hydrogen and R⁷ is alkyl of seven to nineteen carbon atoms,alkenyl of seven to nineteen carbon atoms, 2-methyl-2-propyl,1-adamantyl or phenyl may also be prepared by esterifying with theappropriate acid chloride. The acid chloride dissolved in a solvent suchas methylene chloride, dichloroethane and the like is added to compoundof formula (IX) dissolved in a solvent such as pyridine, lutidines andthe like. The reactants are stirred for 9 to 24 hours, preferably for 16to 24 hours at 15° to 50° C., preferably at room temperature. The aminogroup is deacetylated by treatment with an alcoholic solution of a basesuch as a methanol solution of ammonium hydroxide.

Another method for preparing diesters of formula (I) wherein R⁷ is alkylof seven to nineteen carbon atoms is by reacting compounds of formulas(X) or (XIV) wherein A is hydrogen with the condensation product ofdicyclohexylcarbodiimide, available from Aldrich Chemical Co., and theappropriate carboxylic acid. The carboxylic acid in a molar excess ofdicyclohexylcarbodiimide is added to the above compounds dissolved in asolvent such as dimethylformamide, dimethylacetamide and the like. Thesolution is stirred with heating from 35° to 75° C., preferably from 40°to 60° C. for 16 to 72 hours, preferably for 24 to 60 hours. Thediesters of formula (I) are isolated by precipitation.

Diesters and monoesters of formula (I) wherein R⁷ is an hydroxyalkyl areprepared by first protecting the hydroxy group of the hydroxy acid witha benzyl group, reacting the protected acid with a trityl protectedcompound of formula (X) or (XIV), as described infra, wherein A ishydrogen and removing the benzyl group by catalytic hydrogenationfollowed by removal of the trityl group(s) as discussed above.

The monoester of formula (I) may be prepared by reacting compounds offormula (X) or (XIV) wherein A is hydrogen with a trityl protectivegroup as defined supra. The protective group reacts with the aminonitrogen if present and one hydroxy group. The unprotected hydroxy groupis esterified using an acid chloride by the method described supra. Theprotective groups are removed as described herein above.

The following specific description is given to enable those skilled inthe art to more clearly understand and practice the invention. It shouldnot be considered as a limitation upon the scope of the invention butmerely as being illustrative and representative thereof.

PREPARATION I Preparation of 1,3-Di-O-benzylglycerol

Sodium hydride (100 g (50% dispersion in mineral oil), 2.08 mol) waswashed twice with 1 1 of hexane then dried under nitrogen. Drydimethylformamide (1.5 1) was added. Benzyl alcohol (400 ml) was thenadded at such a rate to keep the temperature below 50° C. The additiontook 2 hours. Epichlorohydrin (92.5 g, 1 mol) was then added dropwiseover 0.5 hour with ice cooling in order to keep the temperature below40° C. The solution was next stirred for 16 hours at 21° C. then for 2.5hours at 50° C. The dimethylformamide was then removed by evaporation atreduced pressure. The oily residue was dissolved in 2.5 1 diethyl ether.The organic solution was washed with 2 l of water, 2 l of 2%hydrochloric acid, 2 l of 1% sodium bicarbonate, and 1 l of brine, driedover sodium sulfate, and concentrated to a brown oil. Distillation gave147.8 g of 1,3-di-O-benzylglycerol (bp 170°-180° C./1 torr).

PREPARATION II Preparation of 1,3-Di-O-benzyl-2-O-chloromethylglycerol

Dry hydrogen chloride gas was bubbled for 1.5 hours into a solution of1,3-di-O-benzylglycerol from Preparation I (15 g, 55 mmol) andparaformaldehyde (3.3 g, 110 mmol) in 175 ml of 1,2-dichloroethane at 0°C. The solution was then stored in a stoppered flask for 21 hours at 4°C. Next, the solution was dried over magnesium sulfate with warming to21° C. then filtered and concentrated to give 17.5 g of1,3-di-O-benzyl-2-O-chloromethylglycerol.

PREPARATION III Preparation of 2-O-Acetoxymethyl-1,3-di-O-benzylglycerol

To a solution of 1,3-di-O-benzyl-2-O-chloromethylglycerol fromPreparation II (17.5 g, 55 mmol) in 400 ml of dimethlyformamide at 0° C.under a drying tube was added sodium acetate (6 g). The solution wasthen warmed to 21° C. and magnetically stirred for 15 hours. The solventwas removed by evaporation at reduced pressure and the oily residuedissolved in 1 pound of diethylether. The ether solution was washed oncewith 750 ml of water, two times with 250 ml of water, and once with 250ml of brine, dried over sodium sulfate and concentrated to give 19 g of2-O-acetoxymethyl-1,3-di-O-benzylglycerol as an oil.

PREPARATION IV Preparation of N²,9-Diacetylguanine

Guanine (20 g, 0.132 mol) was combined with 300 ml of acetic anhydrideand the mixture heated at reflux for 16 hours. The mixture was cooledand the excess acetic anhydride removed by evaporation at reducedpressure. The residue was recrystallized from dimethyl sulfoxide to give25.6 g of N²,9-diacetylguanine.

PREPARATION V A. Preparation of N²-Acetyl-9-(1,3-dibenzyloxy-2-propoxymethyl)guanine

N²,9-Diacetylguanine from Preparation IV (15.61 g, 66 mmol),2-O-acetoxymethyl-1,3-di-O-benzylglycerol from Preparation III (19 g, 55mmol), and bis(p-nitrophenyl)phosphate (0.5 g) were stirred togetherwith 150 ml of diethylether. The solvent was removed by evaporation andthe residue heated in a 175° C. oil bath for 1.5 hours under a stream ofnitrogen. Column chromatography eluting with 1:9 methanol/methylenechloride followed by recrystallization from ethyl acetate afforded 4.76g of N² -acetyl-9-(1,3-dibenzyloxy-2-propoxymethyl)guanine, mp 145°-146°C.

B. Preparation of N² -Acetyl-9-(1,3-dihydroxy-2-propoxymethyl)guanine

To a solution of N² -acetyl-9-(1,3-dibenzyloxy-2-propoxymethyl)guanine(4.62 g, 9.67 mmol) in 150 ml of methanol plus 40 ml of water was added20% palladium hydroxide on carbon as a slurry in 10 ml of water. Themixture was hydrogenated on a Parr hydrogenator at 60 psi of hydrogenfor 38 hours then filtered through celite and concentrated to a whitesolid. Recrystallization from methanol/ethyl acetate gave 1.4 g of N²-acetyl-9-(1,3-dihydroxy-2-propoxymethyl)guanine, mp 205°-208° C.

The mother liquor was further reduced with 10% palladium on carbon (1 g)in 150 ml of methanol plus 50 ml of water at 60 psi for 47 hours. Thetotal yield of N² -acetyl-9-(1,3-dihydroxy-2-propoxymethyl)guanine was2.11 g.

C. Preparation of 9-(1,3-Dihydroxy-2-propoxymethyl)guanine

N² -Acetyl-9-(1,3-dihydroxy-2-propoxymethyl)guanine (721.9 mg, 2.4 mmol)was stirred with 50 ml of methanolic ammonia solution (methanolsaturated with ammonia at 0° C.) for 17 hours at 21° C. The solution wasconcentrated to a white solid and the residue recrystallized from wateror methanol to give 582.3 mg of9-(1,3-dihydroxy-2-propoxymethyl)guanine, mp 250° C.

EXAMPLE 1 9-(1,3-Diacetyloxy-2-propoxymethyl)guanine (Compound WhereinR¹ and R² are Acetyl, R³ is Amino, R⁴ is Hydrogen and R⁵ and R⁶ areKeto)

A mixture of 3.00 g of 9-(1,3-dihydroxy-2-propoxymethyl)guanine, 300 mgof 4-dimethylaminopyridine, and 100 ml of acetic anhydride wasvigorously stirred for 3 days at room temperature. The acetic anhydridewas removed by evaporation at reduced pressure and the residuerecrystallized from methanol to give 3.62 g of9-(1,3-diacetyloxy-2-propoxymethyl)guanine, m.p. 237°-239°.

EXAMPLE 2 9-(1,3-(2,2-dimethylpropanoyloxy)-2-propoxymethyl)guanine(Compound Wherein R¹ and R² are 2,2-dimethylpropanoyl, R³ is Amino, R⁴is Hydrogen, and R⁵ and R⁶ are Keto)

A mixture of 1.306 g of 9-(1,3-dihydroxy-2-propoxymethyl)guanine, 150 mgof 4-dimethylaminopyridine, and 50 ml of 2,2-dimethylpropanoic acidanhydride and dry dimethylformamide (75 ml) was vigorously stirred for 2days. The dimethylformamide was removed by evaporation at reducedpressure, and 200 ml of ethyl ether were added to the residue. Aftercooling to 0° C., the precipitate was isolated by filtration andrecrystallized from methanol to give 1.83 g of9-(1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl)guanine, m.p.230°-232°.

Similarly, using the procedure in Example 1 or 2, substituting theappropriate acid anhydride for acetic anhydride or 2,2-dimethylpropanoicacid anhydride and using compound of Formula (X) or the appropriatecompound of formula (XIV) wherein A is hydrogen the following compounds,for example, are prepared:

2-amino-6-methoxy-9-(1,3-diacetyloxy-2-propoxymethyl)purine;

2-methylamino-6-ethoxy-9-(1,3-dipropanoyloxy-2-propoxymethyl)purine;

2-amino-6-thio-9-(1,3-di-acetyloxy-2-propoxymethyl)purine, m.p.235°-236.5° C.;

2-n-butylamino-6-thio-9-(1,3-di-n-pentanoyloxy-2-propoxymethyl)purine;

2-amino-6-methylthio-9-[1,3-di-2-methylpropanoyloxy)-2-propoxymethyl]purine

2-dimethylamino-6-methylthio-9-[1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl]purine;

2,6-diazido-9-(1,3-di-n-hexanoyloxy-2-propoxymethyl)purine;

2,6-diamino-9-(1,3-diacetyloxy-2-propoxymethyl)purine;

2-methylamino-6-amino-9-(1,3-dipropanoyloxy-2-propoxymethyl)purine;

2-amino-6-methylamino-9-(1,3-di-n-butanoyloxy-2propoxymethyl)purine;

2,6-di(methylamino)-9-[1,3-di-(2-methylpropanoyloxy)-2-propoxymethyl]purine;

6-chloro-2-amino-9-[1,3-diacetyloxy-2-propoxymethyl]purine, m.p.122°-123° C.;

2-chloro-6-methylamino-9-(1,3-di-n-pentanoyloxy-2-propoxymethyl)purine;

2-azido-6-ethylamino-9-(1,3-di-n-hexanoyloxy-2-propoxymethyl)purine;

2-amino-9-[1,3-di-(1-adamantylcarboxy)-2-propoxymethyl]purine;

2-methylamino-9-(1,3-dipropanoyloxy-2-propoxymethyl)purine;

2-dimethylamino-9-(1,3-di-n-butanoyloxy-2-propoxymethyl)purine;

6-amino-9-[1,3-di-(2-methylpropanoyloxy)-2-propoxymethyl]purine;

6-methylamino-9-(1,3-di-n-pentanoyloxy-2-propoxymethyl)purine;

6-dimethylamino-9-[1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl]purine;

6-thio-9-(1,3-di-n-hexanoyloxy-2-propoxymethyl)purine;

6-methylthio-9-(1,3-diacetyloxy-2-propoxymethyl)purine;

9-(1,3-dipropanoyloxy-2-propoxymethyl)guanine, m.p. 191°-193° C.;

9-(1,3-di-n-butanoyloxy-2-propoxymethyl)guanine, m.p. 199°-201° C.;

9-[1,3-di-(2-methylpropanoyloxy)-2-propoxymethyl]guanine;

9-(1,3-di-n-pentanoyloxy-2-propoxymethyl)guanine, m.p. 193°-198° C.;

9-(1,3-di-n-hexanoyloxy-2-propoxymethyl)guanine, m.p. 179°-181° C.;

9-[1,3-di-(4-methylpentanoyloxy)-2-propoxymethyl]guanine, m.p.185.5°-186.5° C.;

9-(1,3-di-methoxyacetyloxy-2-propoxymethyl)guanine, m.p. 183°-185° C.;and

9-[1,3-di-(3-carboxypropanoyoxy)-2-propoxymethyl]guanine, m.p. 140°-144°C.

EXAMPLE 3 9-(1,3-Di-n-hexadecanoyloxy-2-propoxymethyl)guanine

To 50 mg of 9-(1,3-dihydroxy-2-propoxymethyl)guanine in 5 ml ofN,N-dimethylformamide were added 290 mg dicyclohexycarbodiimide and 300mg of n-hexadecanoic acid and the solution was stirred at 50° C. for 50hours. The compound was then precipitated in ice water. The water wasextracted with methylene chloride (3×). The combined methylene chlorideextracts were concentrated, then purified on preparative silica gelplates developed in 1:9 methanol:methylene chloride to yield 140 mg9-(1,3-di-n-hexadecanoyloxy-2-propoxymethyl)guanine, m.p. 150°-154° C.

Similarly, proceeding as in the above example, substituting theappropriate carboxylic acid for n-hexadecanoic acid and using compoundof formula (X) or compounds of formula (XIV) wherein A is hydrogen, thefollowing compounds, for example, are prepared:

2-amino-6-methoxy-9-(1,3-di-n-heptanoyloxy-2-propoxymethyl)-purine;

2-amino-6-chloro-9-(1,3-di-n-octanoyloxy-2-propoxymethyl)purine;

2-amino-6-thio-9-(1,3-di-n-decanoyloxy-2-propoxymethyl)purine;

2-n-butylamino-6-thio-9-(1,3-di-n-dodecanoyloxy-2-propoxymethyl)purine;

2-amino-6-methylthio-9-(1,3-di-n-tetradecanoyloxy-2-propoxymethyl)purine;

2-dimethylamino-6-methylthio-9-(1,3-di-n-hexadecanoyloxy-2-propoxymethyl)purine;

2,6-diazido-9-(1,3-di-n-octadecanoyloxy-2-propoxymethyl)purine;

2,6-diamino-9-(1,3-di-n-eicosanoyloxy-2-propoxymethyl)purine;

2-methylamino-6-amino-9-(1,3-di-n-nonanoyloxy-2-propoxymethyl)purine;

2-amino-9-(1,3-di-n-octanoyloxy-2-propoxymethyl)purine;

2,6-di(methylamino)-9-(1,3-di-n-decanoyloxy-2-propoxymethyl)purine;

2-chloro-6-amino-9-(1,3-di-n-dodecanoyloxy-2-propoxymethyl)purine;

2-chloro-6-methylamino-9-(1,3-di-n-tetradecanoyloxy-2-propoxymethyl)purine;

2-azido-6-ethylamino-9-(1,3-di-n-hexadecanoyloxy-2-propoxymethyl)purine;

6-amino-9-(1,3-di-n-octadecanoyloxy-2-propoxymethyl)purine;

2-methylamino-9-(1,3-n-eicosanoyloxy-2-propoxymethyl)purine;

2-dimethylamino-9-(1,3-di-n-nonanoyloxy-2-propoxymethyl)purine;

2-amino-9-(1,3-di-n-octanoyloxy-2-propoxymethyl)purine;

6-methylamino-9-(1,3-di-n-decanoyloxy-2-propoxymethyl)purine;

6-dimethylamino-9-(1,3-di-n-dodecanoyloxy-2-propoxymethyl)purine;

6-thio-9-(1,3-di-n-tetradecanoyloxy-2-propoxymethyl)purine;

6-methylthio-9-(1,3-di-n-hexadecanoyloxy-2-propoxymethyl)purine;

9-(1,3-di-n-nonanoyloxy-2-propoxymethyl)guanine;

9-(1,3-di-n-octanoyloxy-2-propoxymethyl)guanine, m.p. 165°-166° C.;

9-(1,3-di-n-decanoyloxy-2-propoxymethyl)guanine, m.p. 158°-160° C.;

9-(1,3-di-n-dodecanoyloxy-2-propoxymethyl)guanine, m.p. 162°-164° C.;

9-(1,3-di-n-tetradecanoyloxy-2-propoxymethyl)guanine, m.p. 137°-140° C.;

9-(1,3-di-n-octadecanoyloxy-2-propoxymethyl)guanine; and

9-(1,3-di-n-eicosanoyloxy-2-propoxymethyl)guanine.

EXAMPLE 4 A. N²-(4-methoxyphenyldiphenylmethyl)-9-(1,3-diacetoxy-2-propoxymethyl)guanine

A solution of 3.3 g of 9-(1,3-diacetoxy-2-propoxymethyl)guanine, 7.0 gof 4-methoxyphenyldiphenylmethyl chloride, 7.0 ml of triethylamine and300 mg of 4-dimethylaminopyridine in 50 ml of dry dimethylformamide washeated with magnetic stirring at 50° C. for 15 hours. Methanol (5 ml)was added. The solution was then concentrated at reduced pressure to abrown oil which was chromatographed over silica gel eluting with 1:12methanol:methylene chloride to give an oil. The oil was crystallizedfrom ethyl acetate:hexane to give 5.42 g of N²-(4-methoxyphenyldiphenylmethyl)-9-(1,3-diacetoxy-2-propoxymethyl)guanine,m.p. 139°-141°.

Triphenylmethyl chloride may be substituted for4-methoxyphenyldiphenylmethyl chloride in part A above to prepare thecorresponding triphenylmethyl protected compounds.

Similarly proceeding as above in Part A, substituting the appropriatecompound of formula (XIV) wherein A is acetyl, the following compounds,for example, are prepared:

2-(4-methoxyphenyldiphenylmethylamino)-6-methoxy-9-(1,3-diacetyloxy-2-propoxymethyl)purine;

2-(4-methoxyphenyldiphenylmethylamino)-6-thio-9-(1,3-diacetyloxy-2-propoxymethyl)purine;

2-(4-methoxyphenyldiphenylmethylamino)-6-methylthio-9-(1,3-diacetyloxy-2-propoxymethyl)purine;

2,6-di-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-diacetyloxy-2-propoxymethyl)purine;

2-methylamino-6-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-diacetyloxy-2-propoxymethyl)purine;

2-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-diacetyloxy-2-propoxymethyl)purine;

6-chloro-2-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-diacetyloxy-2-propoxymethyl)purine;

2-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-diacetyloxy-2-propoxymethyl)purine;and

6-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-diacetyloxy-2-propoxymethyl)purine.

B. N²-(4-methoxyphenyldiphenylmethyl)-9-(1,3-dihydroxy-2-propoxymethyl)quanine

A solution of 4.0 g of N²-(4-methoxyphenyldiphenylmethyl)-9-(1,3-diacetoxy-2-propoxymethyl)guaninein 100 ml of methanol plus 20 ml of concentrated ammonium hydroxide wasmagnetically stirred at 22° C. for 16 hours then at 50° C. for 2.5hours. An additional 10 ml of ammonium hydroxide were then added and thesolution stirred another 2.5 hours at 50° C. Next, the solution wasconcentrated at reduced pressure and the residual solid recrystallizedfrom methanol:ethyl acetate to give 3.5 g of N²-(4-methoxyphenyldiphenylmethyl)-9-(1,3-dihydroxy-2-propoxymethyl)guanine,m.p. 148°-151° C.

Similarly proceeding as above in Part B the compounds prepared in Part Amay be hydrolyzed to the following compounds:

2-(4-methoxyphenyldiphenylmethylamino)-6-methoxy-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-(4-methoxyphenyldiphenylmethylamino)-6-thio-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-(4-methoxyphenyldiphenylmethylamino)-6-methylthio-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2,6-di-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-methylamino-6-di-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-dihydroxy-2-propoxymethyl)purine;

6-chloro-2-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-dihydroxy-2-propoxymethyl)purine;and

6-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-dihydroxy-2-propoxymethyl)purine.

C. N²-(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-n-octanoyloxy-2-propoxymethyl)guanine

To a magnetically stirred solution of 1.05 g of N²-(4-methoxyphenyldiphenylmethyl)-9-(1,3-dihydroxy-2-propoxymethyl)guanineand 25 mg of 4-dimethylaminopyridine in 30 ml of dry pyridine was addeddropwise a solution of 1.2 g of n-octanoyl chloride in 10 ml ofmethylene chloride. After 15 hour, 1.5 ml of water was added and thesolution concentrated at reduced pressure. The residue waschromatographed over silica gel eluting with 1:9 methanol:methylenechloride to give a white solid which was recrystallized from ethylacetate:hexane to N²-(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-n-octanoyloxy-2-propoxymethyl)guanine.

Similarly, proceeding as in Part C above, the compounds from Part B maybe esterified to the following compounds:

2-(4-methoxyphenyldiphenylmethylamino)-6-methoxy-9-(1,3-di-n-butanoyloxy-2-propoxymethyl)purine;

2-(4-methoxyphenyldiphenylmethylamino)-6-thio-9-[1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl]purine;

2-(4-methoxyphenyldiphenylmethylamino)-6-thio-9-(1,3-di-n-octanoyloxy-2-propoxymethyl)-2-propoxymethyl)-purine;

2-(4-methoxyphenyldiphenylmethylamino)-6-thio-9-[1,3-di-(1-adamantylcarboxy)-2-propoxymethyl]purine;

2-(4-methoxyphenyldiphenylmethylamino)-6-methylthio-9-(1,3-di-n-heptanoyloxy-2-propoxymethyl)purine;

2,6-di-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-di-n-decanoyloxy-2-propoxymethyl)purine;

2,6-di-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-di-n-octanoyloxy-2-propoxymethyl)purine;

2,6-di-(4-methoxyphenyldiphenylmethylamino)-9-[1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl]purine;

2,6-di-(4-methoxyphenyldiphenylmethylamino)-9-[1,3-di-(1-adamantylcarboxy)-2-propoxymethyl]-purine;

2-methylamino-6-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-di-n-tetradecanoyloxy-2-propoxymethyl)purine;

2-(4-methoxyphenyldiphenylmethylamino)-6-methylamino-9-(1,3-di-n-hexadecanoyloxy-2-propoxymethyl)purine;

6-chloro-2-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-di-n-octadecanoyloxy-2-propoxymethyl)purine;

2-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-di-n-octanoyloxy-2-propoxymethyl)purine;

2-(4-methoxyphenyldiphenylmethylamino)-9-[1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl]purine;

2-(4-methoxyphenyldiphenylmethylamino)-9-[1,3-di-(1-adamantylcarboxy)-2-propoxymethyl]purine;

6-(4-methoxyphenyldiphenylmethylamino)-9-(1,3-di-n-dodecanoyloxy-2-propoxymethyl)purine;

N²-(4-methoxyphenyldiphenylmethyl)-9-(1,3-dipropanoyloxy-2-propoxymethyl)guanine;

N²-(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-n-butanoyloxy-2-propoxymethyl)guanine;

N²-(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-(2-methylpropanoyloxy)-2-propoxymethyl)guanine;

N²-(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-n-pentanoyloxy-2-propoxymethyl)guanine;

N²-(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl)guanine;

N²-(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-n-hexanoyloxy-2-propoxymethyl)guanine;

N²-(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-n-heptanoyloxy-2-propoxymethyl)guanine;

N²-(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-n-decanoyloxy-2-propoxymethyl)guanine;

N²-(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-n-dodecanoyloxy-2-propoxymethyl)guanine;

N²-(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-n-tetradecanoyloxy-2-propoxymethyl)guanine;

N²-(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-n-hexadecanoyloxy-2-propoxymethyl)guanineclear oil;

N²-(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-n-octadecanoyloxy-2-propoxymethyl)guanine;

N²-(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-n-eicosanoyloxy-2-propoxymethyl)guanine;and

N²-(4-methoxyphenyldiphenyl)-9-[1,3-di-(1-adamantylcarboxy)-2-propoxymethyl]guanine;m.p. 201°-203° C.;

N²-(4-methoxyphenyldiphenyl)-9-[1,3-di-(benzyloxyacetyloxy)-2-propoxymethyl]guanine;

N²-(4-methoxyphenyldiphenyl)-9-[1,3-di-(3-benzyloxypropanoyloxy)-2-propoxymethyl]guanine;and

N²-(4-methoxyphenyldiphenyl)-9-[1,3-di-(4-benzyloxybutanoyloxy)-2-propoxymethyl]guanine.

D. 9-(1,3-Di-n-octanoyloxy-2-propoxymethyl)guanine

A solution of 0.969 g of N²-(4-methoxyphenyldiphenylmethyl)-9-(1,3-di-n-octanoyloxy-2-propoxymethyl)guaninein 40 ml of glacial acetic acid plus 10 ml of water was stirred at 75°C. for 3 hours. The solution was then concentrated and the residuechromatographed over silica gel eluting with 1:15 methanol:methylenechloride to give a white solid. The product was recrystallized frommethanol to afford 0.385 g of9-(1,3-di-n-octanoyloxy-2-propoxymethyl)guanine, m.p. 165°-166° C.

Similarly, proceeding as in Part D of the above example, using thecompounds of Part C the following compounds may be prepared:

2-amino-6-methoxy-9-(1,3-di-n-butanoyloxy-2-propoxymethyl)purine;

2-amino-6-thio-9-[1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl]purine;

2-amino-6-thio-9-[1,3-di-n-octanoyloxy-2-propoxymethyl]purine;

2-amino-6-thio-9-[1,3-di-(1-adamantylcarboxy)-2-propoxymethyl]purine;

2-amino-6-methylthio-9-(1,3-di-n-heptanoyloxy-2-propoxymethyl)purine;

2,6-di-amino-9-(1,3-di-n-decanoyloxy-2-propoxymethyl)purine;

2,6-di-amino-9-(1,3-di-n-octanoyloxy-2-propoxymethyl)purine;

2,6-diamino-9-[1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl]purine;

2,6-di-amino-9-[1,3-di-(1-adamantylcarboxy)-2-propoxymethyl]purine;

2-methylamino-6-amino-9-(1,3-di-n-tetradecanoyloxy-2-propoxymethyl)purine;

2-amino-6-methylamino-9-(1,3-di-n-hexadecanoyloxy-2-propoxymethyl)purine;

2-chloro-6-amino-9-(1,3-di-n-octadecanoyloxy-2-propoxymethyl)purine;

2-amino-9-(1,3-di-octanoyloxy-2-propoxymethyl)purine;

2-amino-9-[1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl]purine;

2-amino-9-[1,3-di-(1-adamantylcarboxy)-2-propoxymethyl]purine;

6-amino-9-(1,3-di-n-dodecanoyloxy-2-propoxymethyl)purine;

9-(1,3-dipropanoyloxy-2-propoxymethyl)guanine m.p 191°-193° C.;

9-(1,3-di-n-butanoyloxy-2-propoxymethyl)guanine m.p. 199°-201° C.;

9-[1,3-di-(2-methylpropanoyloxy)-2-propoxymethyl]guanine;

9-(1,3-di-n-pentanoyloxy-2-propoxymethyl)guanine m.p. 193°-198° C.;

9-[1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl]guanine m.p.230°-232° C.;

9-(1,3-di-n-hexanoyloxy-2-propoxymethyl)guanine m.p. 179°-181° C.;

9-(1,3-di-n-heptanoyloxy-2-propoxymethyl)guanine;

9-(1,3-di-n-decanoyloxy-2-propoxymethyl)guanine m.p. 158°-160° C.;

9-(1,3-di-n-dodecanoyloxy-2-propoxymethyl)guanine m.p. 162°-164° C.;

9-(1,3-di-n-tetradecanoyloxy-2-propoxymethyl)guanine 137°-140° C.;

9-(1,3-di-n-hexadecanoyloxy-2-propoxymethyl)guanine m.p. 150°-154° C.;

9-(1,3-di-n-octadecanoyloxy-2-propoxymethyl)guanine;

9-(1,3-di-n-eicosanoyloxy-2-propoxymethyl)guanine;

9-[1,3-di-(1-adamantylcarboxy)-2-propoxymethyl]guanine m.p. 283°-285°C.;

9-[1,3-di-(2-butenoyloxy)-2-propoxymethyl]guanine;

9-[1,3-di-(4-octenoyloxy)-2-propoxymethyl]guanine;

9-[1,3-di-(9-dodecenoyloxy)-2-propoxymethyl]guanine;

9-[1,3-di-(cis-9-hexadecenoyloxy)-2-propoxymethyl]guanine;

9-[1,3-di-(cis-9-octadecenoyloxy)-2-propoxymethyl]guanine;

9-[1,3-di-(9,12-octadecadienoyloxy)-2-propoxymethyl]guanine; and

9-[1,3-di-(9,12,15-octadecatrienoyloxy)-2-propoxymethyl]guanine.

Similarly, catalytically removing the benzyl group and then proceedingas in Part D of the above example the following compounds, for example,are prepared:

9-[1,3-di-(hydroxyacetyloxy)-2-propoxymethyl]guanine;

9-[1,3-di-(3-hydroxypropanoyloxy)-2-propoxymethyl]guanine; and

9-[1,3-di-(4-hydroxybutanoyloxy)-2-propoxymethyl]guanine.

EXAMPLE 5

To 0.26 g of N² -acetyl-9-(1,3-dihydroxy-2-propoxymethyl)guanine frompreparation V, Part B and 10 mg of 4-dimethylaminopyridine in a solutionof 7 ml of pyridine was added 0.764g of adamantanecarboxylic acidchloride as a solution in 3 ml of methylene chloride. The solution wasmagnetically stirred for 18 hours at 21° C. then 1 ml of water wasadded. After stirring an additional hour the solution was concentratedand the residue was treated for 16 hours with 10 ml of methanolcontaining 1 ml of concentrated ammonium hydroxide. The solution wasconcentrated and the residue was triturated with methanol to give 0.277gof 9-[1,3-di(1-adamantylcarboxy)-2-propoxymethyl]guanine, m.p. 283°-285°C.

Similarly, proceeding as above using the appropriate acid chloride andthe appropriate compound of formula (IX) or (XIV) wherein A is hydrogenthe following compounds, for example, are prepared:

2-amino-6-methoxy-9-[1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl]purine;

2-amino-6-thio-9-(1,3-di-n-octanoyloxy-2-propoxymethyl)purine;

2-amino-6-methylthio-9(1,3-di-n-decanoyloxy-2-propoxymethyl)purine;

2,6-diamino-9-(1,3-di-n-dodecanoyloxy-2-propoxymethyl)purine;

2-methylamino-6-amino-9-(1,3-di-n-tetradecanoyloxy-2-propoxymethyl)purine;

2-amino-6-methylamino-9-(1,3-di-n-hexadecanoyloxy-2-propoxymethyl)purine;

2-chloro-6-amino-9-(1,3-di-n-octadecanoyloxy-2-propoxymethyl)purine;

2-amino-9-[1,3-di-(1-adamantylcarboxy)-2-propoxymethyl]purine;

6-amino-9-[1,3-di-(4-octenoyloxy)-2-propoxymethyl]purine;

9-[1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl]guanine;

9-(1,3-di-n-octanoyloxy-2-propoxymethyl)guanine;

9-(1,3-di-n-decanoyloxy-2-propoxymethyl)guanine;

9-(1,3-di-n-dodecanoyloxy-2-propoxymethyl)guanine;

9-(1,3-di-n-tetradecanoyloxy-2-propoxymethyl)guanine;

9-(1,3-di-n-hexadecanoyloxy-2-propoxymethyl)guanine;

9-(1,3-di-n-octadecanoyloxy-2-propoxymethyl)guanine;

9-(1,3-di-n-eicosanoyloxy-2-propoxymethyl)guanine;

9-[1,3-di-(4-octenoyloxy)-2-propoxymethyl]guanine;

9-[1,3-di-(9-dodecenoyloxy)-2-propoxymethyl]guanine;

9-[1,3-di-(cis-9-hexadecenoyloxy)-2-propoxymethyl]guanine;

9-[1,3-di-(cis-9-octadecenoyloxy)-2-propoxymethyl]guanine;

9-[1,3-di-(9,12-octadecadienoyloxy)-2-propoxymethyl]guanine;

9-[1,3-di-(9,12,15-octadecatrienoyloxy)-2-propoxymethyl]guanine; and

9-(1,3-dibenzoyloxy-2-propoxymethyl)guanine, m.p. 242°-243° C.

EXAMPLE 6 A. N²-(4-methoxyphenyldiphenylmethyl)-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-propoxymethyl]guanine

To 2 g of 9-(1,3-dihydroxy-2-propoxymethyl)guanine inN,N-dimethylformamide (50 ml) was added 6.33 g of4-methoxyphenyldiphenylmethyl chloride, 20 mg ofN,N-dimethylaminopyridine, and 10 ml of triethylamine. The reaction wasstirred at 50°-60° C. for 60 hours then precipitated in ice water (900ml). The precipitate was isolated by filtration and the productrecrystallized from ethanol. The slightly impure product was furtherpurified by column chromatography on silica gel eluting with 1:9methanol:methylene chloride to yield 3.5 g N²-(4-methoxyphenyldiphenylmethyl)-9-[1-hydroxy-3-(4-methoxy-phenyldiphenylmethoxy)-2-propoxymethyl]guanineafter recrystallization from methanol, m.p. 159°-161° C.

Similarly, proceeding as in Part A above substituting the appropriatecompounds of formula (XIV) wherein A is hydrogen for9-(1,3-dihydroxy-2-propoxymethyl)guanine and using the appropriateamount of 4-methoxyphenyldiphenylmethyl chloride the following compoundsfor example, are prepared:

2-(4-methoxyphenyldiphenylmethylamino)-6-methoxy-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-propoxymethyl]purine;

2-(4-methoxyphenyldiphenylmethylamino)-6-thio-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-propoxymethyl]purine;

2-(4-methoxyphenyldiphenylmethylamino)-6-methylthio-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-propoxymethyl]purine;

2,6-di-(4-methoxyphenyldiphenylmethylamino)-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-propoxymethyl]purine;

2-methylamino-6-(4-methoxyphenyldiphenylmethylamino)-9-[1-hydroxy-3-(4-methylphenyldiphenylmethoxy)-2-propoxymethyl]purine;

2-(4-methoxyphenyldiphenylmethylamino)-6-methylamino-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-propoxymethyl]purine;

2-chloro-6-(4-methoxyphenyldiphenylmethylamino)-9[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-propoxy-methyl]purine;

2-(4-methoxyphenyldiphenylmethylamino)-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-propoxymethyl]purine;

6-(4-methoxyphenyldiphenylmethylamino)-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-propoxymethyl]purine;

2-methylamino-6-ethoxy-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-propoxymethyl]purine;

2-n-butylamino-6-thio-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-propoxymethyl]purine;

2-dimethylamino-6-methylthio-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-propoxymethyl]purine;

2,6-diazido-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-3-hydroxy-2-propoxymethyl]purine;

2,6-di(methylamino)-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-propoxymethyl]purine;

2-chloro-6-methylamino-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-propoxymethyl]purine;

2-azido-6-ethylamino-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-propoxymethyl]purine;

2-dimethylamino-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-propoxymethyl]purine;

6-methylamino-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-2-propoxymethyl]purine;

6-dimethylamino-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)2-propoxymethyl]purine;

6-thio-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-3-hydroxy-2-propoxymethyl]purine;and

6-methylthio-9-[1-hydroxy-3-(4-methoxyphenyldiphenylmethoxy)-3-hydroxy-2-propoxymethyl]purine.

B. 9-(1-n-Hexadecanoyloxy-3-hydroxy-2-propoxymethyl)guanine

To a stirred mixture of 3 g n-hexadecanoyl chloride in pyridine (50 ml)was added 1.5 g of N²-(4-methoxyphenylmethyl)-9-[hydroxy-3-(4-methoxyphenyldiphenylmethoxy-2-propoxymethyl]guanine.The reaction was stirred 48 hours at 50°-60° C. and then precipitated inice water (500 ml). The resulting precipitate was treated with 80%acetic acid (aqueous) at 80° C. for one hour. The acetic acid wasevaporated under reduced pressure and the residue chromatographed on asilica gel column eluting with 1:9 methanol:methylene chloride to yield0.45 g 9-(1-n-hexadecanoyloxy-3-hydroxy-2-propoxymethyl)guanine afterrecrystallization from methanol m.p. 226°-227° C.

Similarly, proceeding as in Part B above substituting the appropriateacid chloride for n-hexadecanoyl chloride the following compounds, forexample, are prepared:

2-amino-6-methoxy-9-(1-acetyloxy-3-hydroxy-2-propoxymethyl)purine;

2-amino-6-thio-9-[1-(2,2-dimethylpropanoyloxy)-3-hydroxy-2-propoxy-methyl]purine;

2-amino-6-methylthio-9-[1-(2,2-dimethylpropanoyloxy)-3-hydroxy-2-propoxymethyl]purine;

2,6-diamino-9-[1-(2-methylpropanoyloxy)-3-hydroxy-2-propoxymethyl]purine;

2-methylamino-6-amino-9-(1-n-pentanoyloxy-3-hydroxy-2-propoxymethyl)purine;

2-amino-6-methylamino-9-(1-n-hexanoyloxy-3-hydroxy-2-propoxymethyl)purine;

2-chloro-6-amino-9-(1-n-heptanoyloxy-3-hydroxy-2-propoxymethyl)purine;

2-amino-9-(1-n-octanoyloxy-3-hydroxy-2-propoxymethyl)purine;

6-amino-9-(1-n-decanoyloxy-3-hydroxy-2-propoxymethyl)purine;

2-methylamino-9-(1-n-dodecanoyloxy-3-hydroxy-2-propoxymethyl)purine;

2-n-butylamino-6-thio-9-(1-n-tetradecanoyloxy-3-hydroxy-2-propoxymethyl)purine;

2-dimethylamino-6-methylamino-9-(1-n-hexadecanoyloxy-3-hydroxy-2-propoxymethyl)purine;

2,6-diazido-9-(1-octadecanoyloxy-3-hydroxy-2-propoxymethyl)purine;

2,6-di(methylamino)-9-(1-n-eicosanoyloxy-3-hydroxy-2-propoxymethyl)purine;

2-chloro-6-methylamino-9-(1-acetyloxy-3-hydroxy-2-propoxymethyl)purine;

2-azido-6-ethylamino-9-(1-propanoyloxy-3-hydroxy-2-propoxymethyl)purine;

2-dimethylamino-9-(1-n-butanoyloxy-3-hydroxy-2-propoxymethyl)purine;

6-methylamino-9-[1-(2-methylpropanoyloxy)-3-hydroxy-2-propoxymethyl]purine;

6-dimethylamino-9-(1-n-pentanoyloxy-3-hydroxy-2-propoxymethyl)purine;

6-thio-9-[1-(2,2-dimethylpropanoyloxy)-3-hydroxy-2-propoxymethyl]purine;

6-methylthio-9-(1-n-hexanoyloxy-3-hydroxy-2-propoxymethyl)purine;

9-(1-acetyloxy-3-hydroxy-2-propoxymethyl)guanine;

9-(1-n-butanoyloxy-3-hydroxy-2-propoxymethyl)guanine;

9-[1-(2,2-dimethylpropanoyloxy)-3-hydroxy-2-propoxymethyl]guanine;

9-[1-(2-methylpropanoyloxy)-3-hydroxy-2-propoxymethyl]guanine;

9-(1-n-pentanoyloxy)-3-hydroxy-2-propoxymethyl)guanine;

9-(1-n-hexanoyloxy)-3-hydroxy-2-propoxymethyl)guanine;

9-(1-n-heptanoyloxy)-3-hydroxy-2-propoxymethyl)guanine;

9-(1-n-octanoyloxy)-3-hydroxy-2-propoxymethyl)guanine m.p. 215.5°-217.5°C.;

9-(1-n-decanoyloxy)-3-hydroxy-2-propoxymethyl)guanine;

9-(1-n-dodecanoyloxy)-3-hydroxy-2-propoxymethyl)guanine;

9-(1-n-tetradecanoyloxy)-3-hydroxy-2-propoxymethyl)guanine;

9-(1-n-octadecanoyloxy)-3-hydroxy-2-propoxymethyl)guanine;

9-(1-n-eicosanoyloxy)-3-hydroxy-2-propoxymethyl)guanine;

9-(1-methoxyacetyloxy)-3-hydroxy-2-propoxymethyl)guanine;

9-[1-(1-adamantylcarboxy)-3-hydroxy-2-propoxymethyl]guanine;

9-(1-benzoyloxy-3-hydroxy-2-propoxymethyl)guanine;

9-[1-(2-butenoyloxy)-3-hydroxy-2-propoxymethyl]guanine;

9-[1-(4-octenoyloxy)-3-hydroxy-2-propoxymethyl]guanine;

9-[1-(9-dodecenoyloxy)-3-hydroxy-2-propoxymethyl]guanine;

9-[1-(cis-9-hexadecenoyloxy)-3-hydroxy-2-propoxymethyl]guanine;

9-[1-(9,12-octadecadienoyloxy)-3-hydroxy-2-propoxymethyl]guanine;

9-[1-(9,12,15-octadecatrionoyloxy)-3-hydroxy-2propoxymethyl]guanine;

9-[1-(2-butenoyloxy)-3-hydroxy-2-propoxymethyl]guanine; and

9-[1-(3-carboxypropanoyloxy)-3-hydroxy-2-propoxymethyl]guanine m.p.191°-192° C.

Similarly, catalytically removing the benyzl group and then proceedingas above the following compounds, for example, are prepared:

9-(1-hydroxyacetyloxy-3-hydroxy-2-propoxymethyl]guanine;

9-[1-(3-hydroxypropanoyloxy)-3-hydroxy-2-propoxymethyl]guanine; and

9-[1-(4-hydroxybutanoyloxy)-3-hydroxy-2-propoxymethyl]guanine.

EXAMPLE 7

A twofold stoichiometric excess of 3% hydrogen chloride in methanol isadded to a solution of 1.0 g. of9-(1,3-di-n-octanoyloxy-2-propoxymethyl)guanine in 20 ml methanol.Diethyl ether is added until precipitation is complete. The product isfiltered, washed with ether, air dried and recrystallized to give9-(1,3-di-n-octanoyloxy-2-propoxymethyl)guanine hydrochloride.

In a similar manner, all compounds of Formula I in free base form may beconverted to the acid addition salts by treatment with the appropriateacid, for example, hydrochloric acid, hydrobromic acid, sulfuric acid,phosphoric acid, acetic acid, propionic acid, glycolic acid, pyruvicacid, oxalic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid,mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, and the like.

EXAMPLE 8

1.0 g of 9-(1,3-di-n-octanoyloxy-2 propoxymethyl)guanine HCl suspendedin 50 ml of ether is stirred with a twofold stoichiometric excess ofdilute aqueous potassium carbonate solution until the salt is completelydissolved. The organic layer is then separated, washed twice with water,dried over maganesium sulfate and evaporated to yield9-(1,3-di-n-octanoyloxy-2-propoxy methyl)guanine as the free base.

Alkali metal salts of mono and diesters of formula I, particularly whereR⁷ is 1-adamantyl or 2-methyl-2-propyl may be prepared according to thefollowing example.

EXAMPLE 9

The following example illustrates the preparation of representativepharmaceutical formulations containing an active compound of Formula (I)such as 9-[1,3-di-(2,2-dimethylpropanoyloxy-2-propoxymethyl]guanine.

    ______________________________________                                        A. Topical Formulation                                                        ______________________________________                                        Active compound          0.2-2  g                                             Span 60                  2      g                                             Tween 60                 2      g                                             Mineral oil              5      g                                             Petrolatum               10     g                                             Methyl paraben           0.15   g                                             Propyl paraben           0.05   g                                             BHA (butylated hydroxy anisole)                                                                        0.01   g                                             Water qs                 100    ml                                            ______________________________________                                    

All of the above ingredients, except water, are combined and heated at60° C. with stirring. A sufficient quantity of water at 60° C. is thenadded with vigorous stirring to provide 100 g of the cream formulationwhich is then cooled to room temperature.

The following formulation is useful for intraperitoneal andintramuscular injection.

    ______________________________________                                        B. IP and IM Formulation                                                      ______________________________________                                        Active compound        0.5    g                                               Propylene glycol       20     g                                               Polyethylene glycol    20     g                                               Tween 80               1      g                                               0.9% Saline solution qs                                                                              100    ml                                              ______________________________________                                    

The active compound is dissolved in propylene glycol, polyethyleneglycol 400 and Tween 80. A sufficient quantity of 0.9% saline solutionis then added with stirring to provide 100 ml of the I.P or I.M solutionwhich is filtered through a 0.2 micron membrane filter and packagedunder sterile conditions.

The following formulation is useful for intravenous injection.

    ______________________________________                                        C. I.V. Formulation                                                           ______________________________________                                        Active compound        0.1    g                                               Polysorbate 80         0.1    g                                               Propylene glycal or    3.0    g                                               polyethylene glycol 400                                                       Water qs               100    ml                                              ______________________________________                                    

The active compound is added to a solution of polysorbate 80 andpropylene glycol or polyethylene glycol 400 in 20 ml of water and mixed.The resulting solution is diluted with water to 100 ml and filteredthrough the appropriate 0.2 micron membrane filter.

    ______________________________________                                        D. Tablet Formulation                                                                          Parts by weight                                              ______________________________________                                        Active compound    200                                                        Magnesium stearate  3                                                         Starch              30                                                        Lactose            116                                                        PVP (polyvinylpyrrolidone)                                                                        3                                                         ______________________________________                                    

The above ingredients are combined and granulated using methanol as thesolvent. The formulation is then dried and formed into tablets(containing 200 mg of active compound) with an appropriate tablettingmachine.

EXAMPLE 10

The exceptional antiviral activity of the compound of the invention isillustrated by the following assay procedures:

The Herpes simplex virus 2 strain G for infection is prepared in HEp-2cell cultures. Virus is adsorbed for 1 hour, fresh media is placed onthe cells, and they are incubated at 35° C. until all cells wereinfected. The cell suspension is frozen at -70° C., thawed, andcentrifuged to remove cell debris. The supernatant fluid is aliquotedand stored frozen at -70° C. until use. A 10⁶.7 dilution of thesupernatant fluid producer a 50% cell culture infective dose (CCID₅₀) inHEp-2 cells and a 10³.7 dilution producer a 50% lethal challenge (LC₅₀)in mice.

Groups of 20 Swiss Webster female mice (15-17 gm), are challenged byintraperitoneal route using 0.2 ml of EMEM containing 10 LC₅₀ /mouse ofvirus. Mice challenged with 10⁰.5 more or less virus than the 10 LD₅₀challenge serves as a virulence control to assure the model is workingproperly.

Treatment with test compounds begins 6 hours post-challenge. The mice,divided into groups of 20, are administered the compounds in saline s.c.at 5 mg/kg, 10 mg/kg and 20 mg/kg. One group of 20 mice is used as acontrol group and administered saline s.c. The treatment is repeated at24, 48, 72 and 96 hours post-challenge.

Compounds of the instant invention show antiviral activity in the abovetest.

What is claimed is:
 1. A compound of the formula ##STR6## of apharmaceutically acceptable acid addition salt thereof wherein R¹ ishydrogen or --C(O)R⁷ wherein R⁷ is hydrogen, alkyl of one to nineteencarbon atoms, hydroxyalkyl of one to eight carbon atoms, alkoxyalkyl oftwo to nine carbon atoms, alkenyl of two to nineteen carbon atoms,phenyl, or 2-carboxyethyl and the pharmaceutically acceptable alkalimetal salts thereof;R² is --C(O)R⁷ wherein R⁷ is as defined above; R³ isamino; and (a) R⁶ is hydrogen, thio, or amino and R⁴ together with R⁵ isa bond; or (b) R⁵ together with R⁶ is a keto group and R⁴ is hydrogen.2. A compound of claim 1 of the formula ##STR7## wherein R¹ and R² areas defined in claim
 1. 3. A compound of claim 2 wherein R¹ and R² areindependently --C(O)R⁷ wherein R⁷ is as defined in claim
 1. 4. Acompound of claim 3 wherein R⁷ is methyl which is9-(1,3-diacetyloxy-2-propoxymethyl)guanine.
 5. A compound of claim 3wherein R⁷ is ethyl which is9-(1,3-dipropanoyloxy-2-propoxymethyl)guanine.
 6. A compound of claim 3wherein R⁷ is n-propyl which is9-(1,3-di-n-butanoyloxy-2-propoxymethyl)guanine.
 7. A compound of claim3 wherein R⁷ is n-butyl which is9-(1,3-di-n-pentanoyloxy-2-propoxymethyl)guanine.
 8. A compound of claim3 wherein R⁷ is 2-methyl-2-propyl which is9-[1,3-di-(2,2-dimethylpropanoyloxy)-2-propoxymethyl]guanine.
 9. Acompound of claim 3 wherein R⁷ is n-pentyl which is9-(1,3-di-n-hexanoyloxy-2-propoxymethyl)guanine.
 10. A compound of claim3 wherein R⁷ is 3-methyl-1-butyl which is9-(1,3-di-(4-methylpentanoyloxy)-2-propoxymethyl)guanine.
 11. A compoundof claim 3 wherein R⁷ is methoxymethyl which is9-[1,3-di-(methoxyacetyloxy)-2-propoxymethyl]guanine.
 12. A compound ofclaim 3 wherein R⁷ is phenyl which is9-(1,3-dibenzoyloxy-2-propoxymethyl)guanine.
 13. A compound of claim 3wherein R⁷ is n-heptyl which is9-(1,3-di-n-octanoyloxy-2-propoxymethyl)guanine.
 14. A compound of claim3 wherein R⁷ is n-nonyl which is9-(1,3-di-n-decanoyloxy-2-propoxymethyl)guanine.
 15. A compound of claim3 wherein R⁷ is n-undecyl which is9-(1,3-di-n-dodecanoyloxy-2-propoxymethyl)guanine.
 16. A compound ofclaim 3 wherein R⁷ is n-tridecyl which is9-(1,3-di-n-tetradecanoyloxy-2-propoxymethyl)guanine.
 17. A compound ofclaim 3 wherein R⁷ is n-pentadecyl which is9-(1,3-di-n-hexadecanoyloxy-2-propoxymethyl)guanine.
 18. Compound ofclaim 3 wherein R⁷ is 2-carboxyethyl which is9-[1,3-di-(3-carboxypropanoyloxy-2-propoxymethyl]guanine and thepharmaceutically acceptable alkali metal salts thereof.
 19. A compoundof claim 2 wherein R¹ is hydrogen and R² is --C(O)R⁷ wherein R⁷ is asdefined in claim
 1. 20. A compound of claim 19 wherein R⁷ is methylwhich is 9-(1-acetyloxy-3-hydroxy-2-propoxylmethyl)guanine.
 21. Acompound of claim 19 wherein R⁷ is 2-methyl-2-propy which is9-[1-(2,2-dimethylpropanoyloxy)-3-hydroxy-2-propoxymethyl]guanine.
 22. Acompound of claim 19 wherein R⁷ is methoxymethyl which is9-(1-methoxyacetyloxy-3-hydroxy-2-propoxymethyl)guanine.
 23. A compoundof claim 19 wherein R⁷ is n-heptyl which is9-(1-n-octanoyloxy-3-hydroxy-2-propoxymethyl)guanine.
 24. A compound ofclaim 19 wherein R⁷ is n-pentadecyl which is9-(1-n-hexadecanoyloxy-3-hydroxy-2-propoxymethyl)guanine.
 25. A compoundof claim 19 wherein R⁷ is 2-carboxyethyl which is9-[1-(3-carboxypropanoyloxy)-3-hydroxy-2-propoxymethyl]guanine and thepharmaceutically acceptable alkali metal salts thereof.
 26. Apharmaceutical composition which comprises a pharmaceutically acceptablecarrier and a compound of the formula ##STR8## or a pharmaceuticallyacceptable salt thereof wherein R¹ is hydrogen or --C(O)R⁷ wherein R⁷ ishydrogen, alkyl of one to nineteen carbon atoms, hydroxyalkyl of one toeight carbon atoms, alkoxyalkyl of two to nine carbon atoms, alkenyl oftwo to nineteen carbon atoms, phenyl, or 2-carboxyethyl and thepharmaceutically acceptable alkali metal salts thereof;R² is --C(O)R⁷wherein R⁷ is as defined above; R³ is amino, alkyl of one to nineteencarbon atoms or 1-adamantyl; and (a) R⁶ is hydrogen, thio, or amino andR⁴ together with R⁵ is a bond; or (b) R⁵ together with R⁶ is a ketogroup and R⁴ is hydrogen.
 27. A pharmaceutical composition of claim 26which comprises a pharmaceutically acceptable carrier and a compound ofthe formula ##STR9## wherein R¹ and R² are as defined in claim
 26. 28. Apharmaceutical composition of claim 27 wherein R¹ and R² areindependently --C(O)R⁷ wherein R⁷ is as defined in claim
 26. 29. Apharmaceutical composition of claim 28 wherein R⁷ is methyl.
 30. Apharmaceutical composition of claim 28 wherein R⁷ is ethyl.
 31. A methodof treating viral infection in a warm blooded or a cold blooded animalhaving a viral infection which comprises administering an effectiveamount of a compound of the formula ##STR10## or a pharmaceuticallyacceptable salt thereof wherein R¹ is hydrogen or --C(O)R⁷ wherein R⁷ ishydrogen, alkyl of one to nineteen carbon atoms, hydroxyalkyl of one toeight carbon atoms, alkoxyalkyl of two to nine carbon atoms, alkenyl oftwo to nineteen carbon atoms, phenyl, or 2-carboxyethyl and thepharmaceutically acceptable alkali metal salts thereof;R² is --C(O)R⁷wherein R⁷ is as defined above; R³ is amino; and (a) R⁶ is hydrogen,thio, or amino and R⁴ together with R⁵ is a bond; and (b) R⁵ togetherwith R⁶ is a keto group and R⁴ is hydrogen.
 32. A method according toclaim 31 wherein the virus is Herpes Simplex virus I.
 33. A methodaccording to claim 31 wherein the virus is Herpes Simplex virus II. 34.A method according to claim 31 wherein the virus is cytomegalovirus. 35.A method according to claim 31 wherein the virus is Epstein-Barr virus.36. A method according to claim 31 wherein the virus is voricella Zostervirus.
 37. A method according to claim 31 wherein the virus is viralhepatitis.
 38. A method of claim 31 which comprises administering aneffective amount of a compound of the formula ##STR11## wherein R¹ andR² are as defined in claim
 31. 39. A method according to claim 38wherein the virus is Herpes Simplex virus I.
 40. A method according toclaim 38 wherein the virus is Herpes Simplex virus II.
 41. A methodaccording to claim 38 wherein the virus is cytomegalovirus.
 42. A methodaccording to claim 38 wherein the virus is Epstein-Barr virus.
 43. Amethod according to claim 38 wherein the virus is voricella Zostervirus.
 44. A method according to claim 38 wherein the virus is viralhepatitis.
 45. A method of claim 38 wherein R¹ and R² are independently--C(O)R⁷ wherein R⁷ is as defined in claim
 31. 46. A method of claim 45wherein R⁷ is methyl.
 47. A method of claim 45 wherein R⁷ is ethyl.